DESCRIPTION: (Applicant's Abstract) Adolescents with substance use disorders (SUD) and conduct disorder (CD) have high rates of comorbid depression. Despite the high prevalence of depression in such youth, little is known about effective treatment of such depressions. Moreover, the effects of treating depression on substance use and other problem behaviors in such youth are not known. Only serotonergic agents, fluoxetine (FLX) and paroxetine, with most support for FLX, have empirical support in the treatment of depression in adolescents without serious comorbidity. It is not known whether FLX (or paroxetine) are effective in treating the depressions of adolescents with SUD and CD. The proposed study is a randomized, placebo-controlled trial comparing placebo to fluoxetine for major depressive disorder (MDD) in 120 adolescents with SUD and CD. Adolescents with DSM-1V SUD, CD, and MDD assessed both clinically and with structured assessment instruments, will be randomized to one of these two treatment cells for 16 weeks. All subjects will also receive standardized, manual-driven cognitive behavior treatment for adolescent SUD for the duration of the trial as the background "treatment as usual" Medication compliance will be electronically monitored. Adverse side effects will be monitored weekly. The specific aims of this study are to test the following hypotheses: 1. Fidoxeline + CBT will be more effective in treating unipolar depression in adolescents with SUD and CD than placebo + CBT. 2. The treatment of depression with RX + CBT, in depressed adolescents with SUD and CD will be more effective than placebo + CBT in reducing substance use and improving conduct symptoms. 3. The treatment of depression with RX will result in greater retention in, and compliance with substance treatment (CBT) and reduction in both substance use and conduct problems than treatment with placebo. This research will contribute important knowledge regarding effective treatment of depression in conduct-disordered adolescents with SUD and provide information about the effects of treating depression on substance and other behavioral outcomes as well.